Use of ginkgo biloba extracts in order to promote muscle mass to the detriment of fatty mass

ABSTRACT

The invention relates to the use of  Ginkgo biloba  extracts and, in particular,  Ginkgo biloba  extracts comprising between 20 and 30% flavoneglycosides, between 2.5 and 4.5% in total of ginkgolides A, B, C and J, between 2 and 4% bilobalide, less than 10% proanthocyanidins and less than 10 ppm alkylphenol-type compounds, in order to prepare a medicament that is intended to promote muscle mass to the detriment of fatty mass in patients looking to loose or gain weight by means of a diet and/or medical treatment.

The present patent application relates to the use of Ginkgo bilobaextracts for the preparation of a medicament intended to promote musclemass to the detriment of fatty mass.

Obesity is a real public health problem. Certain medicaments do allowstimulation of a weight loss or gain, but the treatment generallyweakens the patients in whom the weight loss or gain occurs often to thedetriment of the ratio of muscle mass to fatty mass.

The Applicant has now discovered that the administration of Ginkgobiloba extracts to subjects trying to lose or gain weight has thebeneficial effect of promoting muscle mass to the detriment of fattymass. Moreover, the Applicant was able to observe that saidadministration stimulates a weight loss in the overweight subject towhom it is administered.

Generally, the invention relates to the use of Ginkgo biloba extractsfor the preparation of a medicament intended to treat weight problems,both in people seeking to gain weight and to lose it.

The invention relates in particular to the use of Ginkgo biloba extractsfor the preparation of a medicament intended for weight loss. Accordingto the invention, the weight loss in the subject treated is at least 4or 5%, and more preferably at least 6, 8 or 10% of their total bodyweight.

According to a particular variant of the invention, the Ginkgo bilobaextracts are used for the preparation of a medicament intended topromote muscle mass to the detriment of fatty mass in patients seekingto lose or gain weight. These patients are optionally subjected to adiet and/or to another medical treatment.

In other words, when, according to the invention, the patient seeking togain or lose weight is treated with a Ginkgo biloba extract concomitantwith their diet or other medical treatment, the ratio R equal to theirmuscle mass M_(m) divided by their total body weight M_(t) tends toremain stable or, in most cases, to increase. Preferably, the increasethus obtained after a period of treatment of at least one month with anextract of Ginkgo biloba will be greater than or equal to 5%, and morepreferably greater than or equal to 6 or 8 or 10%.

The Ginkgo biloba extracts which can be used according to the inventionare such that they comprise at least flavoneglycosides and/or aginkgolide or ginkgolides. Preferably, the flavoneglycosides and/or theginkgolide or ginkgolides are present at least at a level of 25% byweight, more preferably at least at a level of 30% by weight and stillmore preferably at least at a level of 50% by weight in the Ginkgobiloba extract used for the preparation of the medicament according tothe invention. Moreover, the proportion of compounds of alkylphenol typein the Ginkgo biloba extract used according to the invention ispreferably less than 10 ppm, more preferably less than 5 ppm and stillmore preferably less than 1 ppm. If appropriate, the ginkgolide orginkgolides can be replaced with their acetylated homologues, theiralkoxylated homologues or their glycosylated homologues (such as forexample the compounds of general formula (I) described below).

Preferably, the Ginkgo biloba extract used for the preparation of amedicament according to the invention is enriched with flavoneglycosidesand/or ginkgolides. It can for example be an EGb 761® type extract.According to another variant of the invention, the Ginkgo biloba extractused for the preparation of a medicament according to the invention isany Ginkgo biloba extract containing flavoneglycosides, ginkgolides andbilobalide, for example a CP 401 type extract.

By EGb 761® type extract, is meant an extract with a composition more orless identical to that of the standardized EGb 761® extract as it hasbeen defined in particular in the following article: K. Drieu, La pressemédicale, 31, 25 Sep. 1986, supplement dedicated to the Ginkgo bilobaextract (EGb 761®), 1455-1457; or in the European patents EP 431 535 andEP 431 536; by EGb 761® type extract, is therefore meant in particularthe Ginkgo biloba extracts comprising from 20 to 30% offlavoneglycosides, from 2.5 to 4.5% in total of ginkgolides A, B, C andJ, from 2 to 4% of bilobalide, less than 10% of proanthocyanidines andless than 10 ppm (preferably less than 5 ppm and still more preferablyless than 1 ppm) of compounds of alkylphenol type, preferably the Ginkgobiloba extracts comprising from 22 to 36% of flavoneglycosides, from 2.5to 3.5% in total of ginkgolides A, B, C and J, from 2.5 to 3.5% ofbilobalide, less than 8% of proanthocyanidines and less than 10 ppm(preferably less than 5 ppm and still more preferably less than 1 ppm)of compounds of alkylphenol type, and in particular the Ginkgo bilobaextracts comprising approximately 24% of flavoneglycosides, 3.1% intotal of ginkgolides A, B, C and J, 2.9% of bilobalide, 6.5% ofproanthocyanidines and less than 1 ppm of compounds of alkylphenol type.

By CP 401 type extract, is meant extracts such as those which arepresented in the U.S. Pat. No. 5,389,370, in particular the Ginkgobiloba extracts comprising from 5.5 to 8% in total of ginkgolides A, B,C and J, from 40 to 60% of flavoneglycosides and from 5 to 7% ofbilobalide, preferably the Ginkgo biloba extracts comprising from 6.5 to7.5% in total of ginkgolides A, B, C and J, from 45 to 55% offlavoneglycosides and from 5.5 to 6.5% of bilobalide and quiteparticularly the extracts comprising approximately 7 % in total ofginkgolides A, B, C and J, 50% of flavoneglycosides and 6% ofbilobalide.

By extension, the EGb 761® or CP 401 type extracts, the ginkgolides ofwhich have been replaced with their homologues of general formula (I)described later, are also in the same category as the EGb 761® or CP 401type extracts.

According to one variant of the invention, at least part of theginkgolide or ginkgolides can be replaced with the compounds of generalformula (I)

in which W, X, Y and Z independently represent the H, OH, linear orbranched alkoxy or O-G_(S) radicals, G_(S)-OH representing a mono- or adisaccharide, or one of their derivatives or analogues,

it being understood that at least one of W, X, Y or Z represents anO-G_(S) radical.

Preferably, the compounds of general formula (I) described previouslyare such that X represents an OH or O-G_(S) radical, G_(S)-OHrepresenting a mono- or a disaccharide, or one of their derivatives oranalogues, and:

-   -   either W represents an OH or O-G_(S) radical, Y represents H and        Z represents H;    -   or W represents an OH or O-G_(S) radical, Y represents an OH or        O-G_(S) radical and Z represents H;    -   or W represents an OH or O-G_(S) radical, Y represents an OH or        O-G_(S) radical and Z represents an OH or O-G_(S) radical;    -   or W represents an OH or O-G_(S) radical, Y represents H and Z        represents an OH or O-G_(S) radical;    -   or W represents H, Y represents an OH or O-G_(S) radical and Z        represents an OH or O-G_(S) radical;    -   or W represents an OH or O-G_(S) radical, Y represents a linear        or branched alkoxy radical and Z represents H.

For the preparation of the compounds of general formula (I), a personskilled in the art can refer to the PCT Patent Application WO 98/52959or to the U.S. Pat. No. 6.143.725.

According to one aspect of the invention, the patient has weight tolose. In this case, the Ginkgo biloba extract can for example beadministered to the patient in combination with a medicament containingorlistat (for example Xenical®), sibutramine or one of itspharmaceutically acceptable salts (for example Sibutral®),hydroalcoholic extracts of green tea (for example Exolise® or Mincifit®)or from green tea (for example Camiline®), or with any other medicamentintended to stimulate weight loss. Preferably according to theinvention, the Ginkgo biloba extract is administered in combination witha medicament containing orlistat (for example Xenical®), sibutramine orone of its pharmaceutically acceptable salts (for example Sibutral®).However, when the weight to be lost is relatively small (for exampleless than or equal to 5%, or less than or equal to 10% of total bodyweight), the patient can simply receive the Ginkgo biloba extract inaddition to the diet which he has been prescribed.

The invention therefore also relates to a product comprising at leastone Ginkgo biloba extract as described previously in combination with atleast one compound chosen from orlistat, sibutramine or one of itspharmaceutically acceptable salts, hydroalcoholic extracts of green teaor from green tea for a use which is simultaneous, separate or spreadover time in the treatment of excess weight.

By simultaneous therapeutic use, is meant in the present application anadministration of several active ingredients by the same route and atthe same time. By separate use, is meant in particular in the presentapplication an administration of several active ingredients atapproximately the same time by different routes. By therapeutic usespread over time, is meant in the present application an administrationof several active ingredients at different times and in particular anadministration method according to which all the administration of oneof the active ingredients is carried out before the administration ofthe other or others begins. Thus one of the active ingredients can beadministered for several months before administering the other activeingredient or active ingredients. There is no simultaneous treatment inthis case.

According to the other aspect of the invention, the patient has weightto gain. In this case, the Ginkgo biloba extract can be administered tothe patient in combination with a medicament such as fenugreek (forexample Fénugrène®) or any other medicament intended to stimulate weightgain. However, when the weight to be gained is relatively small (forexample less than or equal to 5%, or less than or equal to 10% of thetotal body weight), the patient can simply receive Ginkgo biloba extractin addition to the diet which he has been prescribed.

The invention therefore also relates to a product comprising at leastone Ginkgo biloba extract as described previously in combination withfenugreek for a use which is simultaneous, separate or spread over timein the treatment of a weight deficiency.

According to the invention, the patient who has weight to lose or togain can be an animal or a human. Among the animals for which theinvention can be used, in particular there may be mentioned dogs, cats,bovines, ovines, poultry (chickens, turkeys, ducks, etc.) or horses.Preferably, the patient is a human.

The pharmaceutical compositions comprising a Ginkgo biloba extract canbe in the form of solids, for example powders, granules, tablets,gelatin capsules, liposomes, suppositories or patches. Appropriate solidsupports can be, for example, calcium phosphate, magnesium stearate,talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine and wax.

The pharmaceutical compositions comprising a Ginkgo biloba extract canalso be in liquid form, for example, solutions, emulsions, suspensionsor syrups. Appropriate liquid supports can be, for example, water,organic solvents such as glycerol or glycols, as well as their mixtures,in varying proportions, in water.

The administration of a medicament according to the invention can becarried out by topical, oral, parenteral route, by injection(intramuscular, sub-cutaneous, intravenous, etc.), etc.

The daily dosage of Ginkgo biloba extract envisaged is comprised between0.1 mg to 10 g according to the concentration of active ingredient ofthe extract and the seriousness of the weight problems of the subject tobe treated. The final decision will be made by the attending doctor orveterinarian.

The term “approximately” refers to an interval around the valueconsidered. As used in the present application, “approximately X”signifies an interval of X minus 10% of X to X plus 10% of X, andpreferably an interval of X minus 5% of X to X plus 5% of X.

Unless it is specified otherwise, all the technical and scientific termsused here have the same meaning as that usually understood by aspecialist in the field to which this invention belongs. Similarly, allthe publications, patent applications, all the patents and all otherreferences mentioned here are incorporated by way of reference.

In order to show the benefit of the use of Ginkgo biloba extracts asdescribed previously in the treatment of weight problems, the testdescribed hereafter can be carried out. Other tests which aim forexample to determine the body composition and in particular the ratio offatty mass to non-fatty mass (cf. Chumlea et al., Nutrition, Health &Aging, 1(1), 7-12) can also be carried out in order to achieve the sameresult.

Pharmacological Section

Comparitive Measurement of the Development of Body Weight in Aged RatsTreated or not Treated with EGb 761:

The aged laboratory rats have, due to their captivity, a naturaltendency to gain weight. Two groups of aged (22 months) Wistar rats arecreated, one being constituted by 11 rats which receive normal drinkingwater for 5 weeks and the other being constituted by 12 rats whichreceive drinking water containing 75 mg per kg of standardized Ginkgobiloba extract EGb 761®. The rats are weighed before the start and afterthe end of the treatment.

Results Obtained:

i) The measurements of the weight of the rats produce the followingresults: Non-treated aged Treated rats aged rats Average weight at 22months (g) 605.64 594.10 Average weight at 22 months and 5 619.33 570.11weeks (g)

In other words, in the space of a few weeks, the non-treated rats havegained 2.2% in body weight while the treated rats have lost 4% of theirbody weight.

ii) Moreover, it is observed above all that the ratio of muscle weightin relation to the total body weight is 0.53 in the treated ratscompared to 0.42 for the non-treated rats.

Consequently, it is seen that a treatment with the standardized Ginkgobiloba extract EGb 761® does allow, on the one hand, weight loss in therats which have a tendency to become obese, and, on the other hand, apromotion of their muscle mass to the detriment of their fatty mass.

1. (canceled)
 2. The method of claim 11, wherein the flavoneglycosidesand/or the ginkgolide or ginkgolides are present at least at a level of25% by weight in the Ginkgo biloba extract.
 3. The method of claim 11,wherein the Ginkgo biloba extract comprises from 20 to 30% offlavoneglycosides, from 2.5 to 4.5% in total of ginkgolides A, B, C andJ, from 2 to 4% of bilobalide, less than 10% of proanthocyanidines andless than 10 ppm of compounds of alkylphenol type.
 4. The method ofclaim 3, wherein at least one part of the ginkgolides A, B, C and J isreplaced with the compounds of the formula

wherein W, X, Y and Z are independently selected from the groupconsisting of H, OH, alkoxy and —O-G_(S) radicals, G_(S)-OH being amono- or a disaccharide, or one of their derivatives or analogues, itbeing understood that at least one of W, X, Y or Z is —O-G_(S).
 5. Themethod of claim 4, wherein the compounds of formula (I) are such that Xis —OH or —O-G_(S), G_(S)-OH being a mono- or a disaccharide, or one oftheir derivatives or analogues, and: either W is —OH or —O-G_(S), Y is Hand Z is H; or W is —OH or —O-G_(S), Y is —OH or —O-G_(S) and Z is H; orW is —OH or —O-G_(S), Y is —OH or —O-G_(S) and Z is —OH or —O-G_(S); orW is —OH or —O-G_(S), Y is H and Z is —OH or —O-G_(S); or W is H, Y is—OH or —O-G_(S) and Z is —OH or —O-G_(S); or W is —OH or —O-G_(S), Y isalkoxy and Z is H.
 6. The method of claim 11, wherein the Ginkgo bilobaextract comprises from 5.5 to 8% in total of ginkgolides A, B, C and J,from 40 to 60% of flavoneglycosides and from 5 to 7% of bilobalide. 7.The method of claim 6, wherein a part at least of the ginkgolides A, B,C and J is replaced with the compounds of the formula

wherein W, X, Y and Z are independently selected from the groupconsisting of H, OH, alkoxy and —O-G_(S), G_(S)-OH being a mono- or adisaccharide, or one of their derivatives or analogues, it beingunderstood that at least one of W, X, Y or Z is —O-G_(S).
 8. The methodof claim 7, wherein the compounds of formula (I) are such that X is —OHor —O-G_(S), G_(S)-OH being a mono- or a disaccharide, or one of theirderivatives or analogues, and: either W is —OH or —O-G_(S), Y is H and Zis H; or W is —OH or —O-G_(S), Y is —OH or —O-G_(S) and Z is H; or W is—OH or —O-G_(S), Y is —OH or —O-G_(S) and Z is —OH or —O-G_(S); or W is—OH or —OG_(S), Y is H and Z is —OH or —O-G_(S), or W is H, Y is —OH or—O-G_(S) and Z is —OH or —O-G_(S); or W is —OH or —O-G_(S), Y is alkoxyand Z is H.
 9. The method of claim 11 wherein the warm-blooded animalsare people seeking to lose weight.
 10. The method of claim 11 whereinthe warm-blooded animals are people seeking to gain weight.
 11. A methodof promoting muscle mass to the detriment of fatty mass in warm-bloodedanimals comprising administrating to warm-blooded in need thereof aneffective amount of a Ginkgo extract comprising at least one member orthe group consisting of flavoneglycosides, ginkgolide and ginkgolides totreat weight problems.